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Objectives: To compare the clinical characteristics and prognosis of women with clear cell versus high-grade serous ovarian carcinoma.Methods: Retrospective analysis of the clinical data of 50 cases patients with ovarian clear cell carcinoma (OCCC) and 103 cases with high-grade serous ovarian carcinoma (HGSOC), who were initially treated and completed standardized therapy in Affiliated Hospital of Qingdao University from January 2013 to December 2017.Results: There were significant differences in age, gravidity (G > 1), chief complaint, with ovarian endometriosis, tumor diameter, unilateral or bilateral, cystic and solid tumor, CA125, HE4, CA199, lactate dehydrogenase (LDH), and FIGO stage between the two groups. The differences in the prognosis between OCCC patients and HGSOC patients with early stage (FIGO I-II) were not statistically significant. The 5-year overall survival and progression-free survival of OCCC patients were significantly worse than those of HGSOC patients with advanced stage (FIGO III-IV) (P < 0.05). FIGO stage and non-R0 resection were independent risk factors affecting the prognosis of patients with ovarian clear cell carcinoma, screening by Cox regression analysis. FIGO stage, the lowest value of CA125, and non-R0 resection were independent risk factors affecting the prognosis of patients with high-grade serous ovarian cancer.Conclusions: The clinical characteristics and prognosis of OCCC are different from those of HGSOC. OCCC patients have a significantly worse prognosis than those with HGSOC in the advanced stage (FIGO Ⅲ-Ⅳ). Satisfactory tumor resection is an essential factor related to the prognosis of patients with OCCC and HGSOC.

Background Chlamydia trachomatis (Ct) infection ascending to the upper genital tract can cause infertility. Direct association of genetic variants as contributors is challenging because infertility may not be diagnosed until years after infection. Investigating the intermediate trait of ascension bridges this gap. Methods We identified infertility genome-wide association study (GWAS) loci using deoxyribonucleic acid from Ct-seropositive cisgender women in a tubal factor infertility study and Ct-infected cisgender women from a longitudinal pelvic inflammatory disease cohort with known fertility status. Deoxyribonucleic acid and blood messenger ribonucleic acid from 2 additional female cohorts with active Ct infection and known endometrial infection status were used to investigate the impact of infertility single-nucleotide polymorphisms (SNPs) on Ct ascension. A statistical mediation test examined whether multiple infertility SNPs jointly influenced ascension risk by modulating expression of mediator genes. Results We identified 112 candidate infertility GWAS loci, and 31 associated with Ct ascension. The SNPs altered chlamydial ascension by modulating expression of 40 mediator genes. Mediator genes identified are involved in innate immune responses including type I interferon production, T-cell function, fibrosis, female reproductive tract health, and protein synthesis and degradation. Conclusions We identified Ct-related infertility loci and their potential functional effects on Ct ascension.

Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme’s catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-021-02508-5.

Friedreich ataxia (FRDA) is a serious hereditary neurodegenerative disease, mostly accompanied with hypertrophic cardiomyopathy, caused by the reduced expression of frataxin (FXN). However, there is still no effective treatment. Our previous studies have shown that SS-31, a mitochondrion-targeted peptide, is capable to upregulate the expression of FXN and improve the mitochondrial function in cells derived from FRDA patients. To further explore the potential of SS-31, we used the GAA expansion-based models, including Y47 and YG8R (Fxn KIKO) mice, primary neurons and macrophages from the mice and cells derived from FRDA patients. After once-daily intraperitoneal injection of 1 mg/kg SS-31 for 1 month, we observed the significant improvement of motor function. The vacuolation in dorsal root ganglia, lesions in dentate nuclei and the lost thickness of myelin sheath of spinal cord were all repaired after SS-31 treatment. In addition, the hypertrophic cardiomyocytes and disarrayed abnormal Purkinje cells were dramatically reduced. Interestingly, we found that SS-31 treatment upregulated FXN expression not only at the translational levels as observed in cell culture but also at mRNA levels in vivo. Consequently, mitochondrial morphology and function were greatly improved in all tested tissues. Importantly, our data provided additional evidence that the maintenance of the therapeutic benefits needed continuous drug administration. Taken together, our findings have demonstrated the effectiveness of SS-31 treatment through the upregulation of FXN in vivo and offer guidance of the potential usage in the clinical application for FRDA.

Risperidone and aripiprazole, commonly used antipsychotics in children with autism spectrum disorder (ASD), have previously been associated with elevated fracture risk in other populations. The aim of this study was to evaluate and compare the risk of fracture among children with ASD using risperidone or aripiprazole. This was a retrospective, propensity-score matched cohort study, set between January 2013 and December 2018. We used the MarketScan Medicaid insurance data, which covers multiple states of the United States. We included ASD children aged 2-18 years, who were new users of aripiprazole or risperidone and with no prior history of antipsychotic use or fractures. The main exposure was the continued use of aripiprazole or risperidone. The incidence rates of any fracture during follow-up were evaluated, and the risk between aripiprazole and risperidone was compared via Cox-proportional hazard models. Results were stratified by age, sex, duration of exposure and fracture site. In total, 3312 patients (78% male; mean [SD] age 11.0 [3.7] years) were identified for each cohort. Over the full duration of follow-up, fracture incidence rates per 1000 patient-years were 23.2 for risperidone and 38.4 for aripiprazole (hazard ratio and 95% confidence interval: 0.60 [0.44-0.83]). Risks were similar between cohorts throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. Extremity fractures drove most of the increased risk, with the biggest differences in lower leg and ankle fractures. Differences widened for children aged 10 years or younger (HR [95% CI]: 0.47 [0.30-0.74]). In conclusion, compared to aripiprazole, risperidone was associated with 40% lower risk of fracture. Further analysis on the mechanism and long-term bone health of antipsychotic-treated children with ASD is warranted.Lay summary We compared the risk of bone fractures among 6624 children with autism spectrum disorder (ASD), half of whom used risperidone and half of whom used aripiprazole. Taking other factors into account, risks were similar between the two groups throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. The biggest differences were in lower leg and ankle fractures. Overall, compared with aripiprazole, risperidone was associated with 40% lower risk of fracture.

OBJECTIVE: Antiretroviral drug (ARV) theranostics facilitates the monitoring of biodistribution and efficacy of therapies designed to target human immunodeficiency virus type-1 (HIV-1) reservoirs. To this end, we have now deployed intrinsic drug chemical exchange saturation transfer (CEST) contrasts to detect ARVs within the central nervous system (CNS). DESIGN AND METHODS: CEST effects for lamivudine (3TC) and emtricitabine (FTC) were measured by asymmetric magnetization transfer ratio analyses. The biodistribution of 3TC in different brain sub-regions of C57BL/6 mice treated with lipopolysaccharides was determined using magnetic resonance imaging (MRI). CEST effects of 3TC protons were quantitated by Lorentzian fitting analysis. 3TC levels in plasma and brain regions were measured using ultraperformance liquid chromatography tandem mass spectrometry to affirm the CEST test results. RESULTS: CEST effects of the hydroxyl and amino protons in 3TC and FTC linearly correlated to drug concentrations. 3TC was successfully detected in vivo in brain sub-regions by MRI. The imaging results were validated by measurements of CNS drug concentrations. CONCLUSION: CEST contrasts can be used to detect ARVs using MRI. Such detection can be used to assess spatial-temporal drug biodistribution. This is most notable within the CNS where drug biodistribution may be more limited with the final goal of better understanding ARV-associated efficacy and potential toxicity.

The metabolism of chlorogenic acid (CGA) through the intestinal tract was studied. As cadmium is a well-known toxic heavy metal, this study was carried out to investigate the comparative protective effect of CGA and its representative intestinal metabolite (3-(3-hydroxyphenyl) propionic acid, HPPA) against Cd-induced erythrocyte cytotoxicity in vitro and in vivo. We found that CGA and its intestinal metabolite appreciably prevented erythrocyte hemolysis, osmotic fragility, and oxidative stress induced by Cd. Also, we found that HPPA had a stronger protective ability than CGA against Cd-induced erythrocyte injury in vivo, such as increasing the ratio of protein kinase C from 7.7% (CGA) to 12.0% (HPPA). Therefore, we hypothesized that CGA and its microbial metabolite had protective effects against Cd-induced erythrocyte damage via multiple actions including antioxidation and chelation. For humans, CGA supplementation may be favorable for avoiding Cd-induced biotoxicity.

To investigate the efficacy and safety of prostatic artery embolization (PAE) vs. transurethral resection of the prostate (TURP) in patients affected by benign prostatic hyperplasia (BPH). We also reviewed mean changes from baseline in PAE at selected follow-up points. PubMed, Web of Science, and Embase were searched up to May 1, 2020. Randomized controlled trials on PAE were collected according to specific inclusion and exclusion criteria. Meta-analyses were performed using RevMan 5.3, STATA 14, and GraphPad Prism 8. Pooled patient-reported scores and functional outcomes were calculated by using a fixed or random-effect model. Eleven articles met our selection criteria and ten independent patient series were included in the final analysis. Pooled estimates suggested no significant difference between TURP and PAE for patient-reported outcomes including International Prostate Symptom Score (2.32 (− 0.44 to 5.09)) and quality of life (0.18 (− 0.41 to 0.77)) at 12 months. PAE was less effective regarding improvements in most functional outcomes such as maximum flow rate, prostate volume, and prostate-specific antigen. Moreover, PAE may be associated with relatively fewer complications, lower cost, and shorter hospitalization. After the PAE procedure, the overall weighted mean differences for all outcomes except sexual health scores were significantly improved from baseline during follow-up to 24 months. PAE is non-inferior to TURP with regard to improving patient-reported outcomes, though most functional parameters undergo more changes after TURP than after PAE. Moreover, PAE can significantly continue to relieve symptoms for 24 months without causing serious complications. • PAE is as effective as TURP in improving subjective symptom scores, with fewer complications and shorter hospitalization times. • PAE is inferior to TURP in the improvement of most functional outcomes. • Improvements due to PAE are durable during follow-up to 24 months.

Heterostructural engineering and noble metal coupling are effective strategies to optimize semiconductor photocatalytic materials. In this work, (Ag, Mn2O3)-codecorated ZnO nanoparticles with different Mn2O3 contents (0–10 mol%) were synthesized by integrating the two strategies by a facile two-step polymer network-gel process. The photocatalytic activity of Ag/ZnO (AZM0) was significantly enhanced with the optimum Mn2O3 molar ratio of 3 mol%. The degradation efficiency of AZM3 is ∼3 times and ∼4.8 times higher than that of AZM0 for the degradation of methylene blue (MB) upon exposure to simulated sunlight and visible light, respectively. Also, this ternary nanocomposite exhibits enhanced gas sensing performance towards NO2 under ultraviolet/visible light irradiation at room temperature. The analysis of its microstructural, optical and photoelectrical characteristics suggests the synergistic coupling effects of Ag and Mn2O3, in which the significantly enhanced visible light response and hetero-interface charge carrier migration are the critical factors for the improvement of photocatalytic efficiency and gas sensing activity. Furthermore, the effects of recycling ability, the influence of the initial solution pH, the catalyst dosage and the main active species during the catalysis process on photocatalytic activity were explored. This study develops a feasible pathway to consciously construct multiheterostructures for enhancing the photocatalytic activity with great potential applications in toxic pollution abatement and noxious gas detection.

Multiple sclerosis (MS) is the most common autoimmune disorder affecting the central nervous system. Epstein-Barr virus (EBV) is a causative agent for infectious mononucleosis (IM) that is associated with MS pathogenesis. However, the exact mechanism by which EBV, specifically in IM, increases the risk for MS remains unknown. EBV immortalizes primary B lymphocytes in vitro and causes excessive B lymphocyte proliferation in IM in vivo. In asymptomatic carriers, EBV-infected B lymphocytes still proliferate to certain degrees, the process of which is tightly controlled by the host immune systems. Experimental autoimmune encephalomyelitis (EAE) mimics key features of MS in humans and is a well-established rodent model for human MS. We have found that xenografts of EBV-immortalized B lymphocytes, which partially resemble the hyperproliferation of EBV-infected cells in IM, exacerbate autoimmune responses in myelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice. After remission, an additional challenge with EBV-immortalized cells induces a relapse in EAE. Moreover, xenografts with EBV-immortalized cells tighten the integrity of the blood-brain barrier (BBB) in the thalamus and hypothalamus areas of the mouse brains. Genomic sequences of prokaryotic 16S ribosomal RNA presented in the feces reveal that EBV-immortalized cells significantly change the diversities of microbial populations. Our data collectively suggest that EBV-mediated proliferation of B lymphocytes may be a risk factor for the exacerbation of MS, which are associated with gut microbiome changes and BBB modulations. Furthermore, multiple xenografts of EBV-immortalized cells into C57BL/6 mice could serve as a useful model for human relapsing-remitting MS with predictable severity and timing.

Background: We compared women's acceptability of urine and cervico-vaginal sample self-collection for high-risk (oncogenic) human papillomavirus (hrHPV) testing and assessed whether acceptability v...

Background Botulinum toxin type A (BTA) injection is a widely-used procedure to correct cosmetic problems caused by muscular hyperactivity. "Cobblestone chin" refers to the appearance of remarkable chin creases caused by mentalis contraction. Aims The aim of this case report is to raise the awareness of paradoxical bulging after BTA injection in mentalis. Patient/methods A 26-year-old female asked for cosmetic correction of the "cobblestone chin". BTA injection was performed routinely to the mentalis muscle. However, on the second day after injection, an unusual paradoxical bulging at chin was presented. Results We speculated that the imbalanced relaxation of mentalis caused by improper injection and uneven diffusion of BTA is responsible for the bulging. After a supplementary injection of BTA in the remaining hyperactive muscle fibers based on the ultrasound examination, the bulging was relieved and chin contour improved significantly. Conclusion Injection of BTA in mentalis should cover the whole thickness of the muscle to prevent imbalanced paralysis and paradoxical chin bulging, especially in severe mentalis hyperactivity cases.

Background/aimsThe aim of this study was to generate and evaluate individualised post-therapeutic optical coherence tomography (OCT) images that could predict the short-term response of antivascular endothelial growth factor therapy for typical neovascular age-related macular degeneration (nAMD) based on pretherapeutic images using generative adversarial network (GAN).MethodsA total of 476 pairs of pretherapeutic and post-therapeutic OCT images of patients with nAMD were included in training set, while 50 pretherapeutic OCT images were included in the tests set retrospectively, and their corresponding post-therapeutic OCT images were used to evaluate the synthetic images. The pix2pixHD method was adopted for image synthesis. Three experiments were performed to evaluate the quality, authenticity and predictive power of the synthetic images by retinal specialists.ResultsWe found that 92% of the synthetic OCT images had sufficient quality for further clinical interpretation. Only about 26%–30% synthetic post-therapeutic images could be accurately identified as synthetic images. The accuracy to predict macular status of wet or dry was 0.85 (95% CI 0.74 to 0.95).ConclusionOur results revealed a great potential of GAN to generate post-therapeutic OCT images with both good quality and high accuracy.

Aβ plaques of Alzheimer's disease (AD) are believed to precede cognitive deficits or clinical manifestation by decades. However, validated biomarkers for early diagnosis of the AD disease are still not available. In this present study, we combined MRI-based neuroimages and histological assessment of the glial response and altered cytokines, neurogenesis during the early course of Aβ deposits in TgAPP/PS1 mice to find potential early biomarkers for AD. We found that microglia and astrocytes were initially activated and clustered around Aβ plaques at the age of 6 months and significantly increased with age from 6-12 months of age. Confocal microscope analysis revealed that microglia not astrocytes began to phagocytose Aβ in 6-month-old TgAPP/PS1 mice, evidenced by the intracellular Aβ in Iba1 positive microglia not in GFAP positive astrocytes. In parallel with these observations, we found that mainly clustered microglia significantly upregulated the production of proinflammatory factors including TNF-α, iNOS and IL-1β, and anti-inflammatory cytokines including IL-4, TGF-β and extracellular protecting matrix YM-1 and enzyme arginase 1 (Arg1) at 6-12 months of age. Interestingly, reactive astrocyte did not express these cytokines and YM-1 and Arg1. These results may suggest that microglia rather than astrocytes play crucial roles in clearing Aβ and neuroinflammation in early stage of AD. In addition, the number of neural stem cells labeled by BrdU and immature neurons labeled by doublecortin was significantly decreased in 3-month-old TgAPP/PS1 mice ahead of Aβ deposits. Finally, DTI conforms that reduced fractional anisotropy (FA) in dentate gyrus of hippocampus and rs-MRI shows an increased connectivity in the networks of somatosensory cortex-caudoputamen and insula in TgAPP/PS1 mice at 6 months. These findings provide a clue to early biomarkers for diagnosis of the AD disease.

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. Methods In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb–KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. Results The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. Conclusions These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs. Graphical Abstract

Background: Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represent a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. However, the role of TRPC3 in acute and chronic itch is still not well defined. Methods: RNAscope in situ hybridization and immunohistochemical staining were performed on mouse trigeminal ganglion (TG) neurons. Fura-2 calcium imaging was used to characterize the function of TRPC3 in dissociated TG neurons. In native mice, the TRPC3 agonist and pruritogens were subcutaneously injected to the cheek and nape of the neck of mice, respectively. Site directed scratching and/or wiping behaviors were video recorded. Contact hypersensitivity (CHS) model was induced in mouse ears by topical application of SADBE or DNCB. Spontaneous scratching behaviors were recorded by video monitoring. Global and conditional Trpc3 knockout mice were employed to determine the contribution of TRPC3 to acute and chronic itch. The mRNA expression levels of Trpc3 and proinflammatory cytokines were assayed by quantitative real-time PCR. H&E. staining was used for the evaluation of the thickness of mouse ears. Flow cytometry was performed to assess immune cell infiltration in mouse ear tissues. Results: Among mouse TG neurons, RNAscope assay revealed that Trpc3 mRNA was predominantly expressed in nonpeptidergic small diameter neurons. Moreover, Trpc3 mRNA signal was present in the majority of itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch- and pain-like behaviors in naïve mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of CHS, Trpc3 mRNA expression level and function were upregulated in the TG following CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. Conclusions: These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch via a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.

Background Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment. Methods We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM’s specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to its specificity against HDAC1 and HDAC2, but not HDAC11, and blood-brain barrier permeability. Results We tested PCI-24781 using in vitro human and mouse GBM syngeneic cell lines, an in vivo murine orthograft, and a genetically engineered mouse model for GBM (PEPG - PTENflox/+; EGFRvIII+; p16Flox/− & GFAP Cre +). PCI-24781 significantly inhibited tumor growth and downregulated DNA repair machinery (BRCA1, CHK1, RAD51, and O6-methylguanine-DNA- methyltransferase (MGMT)), increasing DNA double-strand breaks and causing apoptosis in the GBM cell lines, including an MGMT expressing cell line in vitro. Further, PCI-24781 decreased tumor burden in a PEPG GBM mouse model. Notably, TMZ + PCI increased survival in orthotopic murine models compared to TMZ + vorinostat, a pan-HDAC inhibitor that proved unsuccessful in clinical trials. Conclusion PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation.

Iron regulatory protein 2 (IRP2) deficiency in mice and humans causes microcytic anemia and neurodegeneration due to functional cellular iron depletion. Our previous in vitro data have demonstrated that Irp2 depletion upregulates hypoxia-inducible factor subunits Hif1α and Hif2α expression; inhibition of Hif2α rescues Irp2 ablation-induced mitochondrial dysfunction; and inhibition of Hif1α suppresses the overdose production of lactic acid derived from actively aerobic glycolysis. We wonder whether Hif1α and Hif2α are also elevated in vivo and play a similar role in neurological disorder of Irp2–/– mice. In this study, we confirmed the upregulation of Hif2α, not Hif1α, in tissues, particularly in the central nervous system including the mainly affected cerebellum and spinal cord of Irp2–/– mice. Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented neurodegenerative symptoms, which were proved by Purkinje cell arrangement from the shrunken and irregular to the full and regular array. PT-2385 treatment did not only modulate mitochondrial morphology and quality in vivo but also suppressed glycolysis. Consequently, the shift of energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) was reversed. Our results indicate that Irp2 depletion-induced Hif2α is, in vivo, in charge of the switch between OXPHOS and glycolysis, suggesting that, for the first time to our knowledge, Hif2α is a clinically potential target in the treatment of IRP2 deficiency-induced neurodegenerative syndrome.

Background To adapt to daily changes in the external environment, organisms have developed circadian rhythm systems with a period of approximately 24 h. Many studies have reported that both circadian rhythms and exosomes play important roles in the development and metastasis of tumors. However, whether circadian clock genes can affect the progression of tumors by regulating exosomes remains unclear. Methods and results In this study, we isolated exosomes from the supernatant of human colorectal cancer (CRC) cells, including SW480, SW620, and HCT116 cells, by differential centrifugation and characterized exosomes by transmission electron microscopy, nanoparticle tracking analysis, and Western blot analysis. Then, we found that exosomes derived from SW480, SW620 and HCT116 cells could promote the migration of HCT116 and human umbilical vein endothelial cells. Exosomes derived from SW620 cells showed increased stimulating effects when we increased the expression of BMAL1, a core circadian protein. In contrast, exosomes derived from SW480 and HCT116 cells showed decreased stimulating effects when we knocked down the expression of BMAL1. Furthermore, we discovered that BMAL1 promotes the release of exosomes by HCT116 and SW620 cells. In addition, by luciferase assay, we confirmed that BMAL1 transcriptionally regulates the expression of Rab27a, a key molecule related to the secretion of exosomes. Conclusions Our data reveal a new mechanism by which BMAL1 induces CRC metastasis by stimulating exosome secretion. This finding may help further clarify the role of circadian rhythm in the progression of CRC.

Over 50% of colorectal cancer patients develop resistance after a transient response to therapy. Understanding tumor resistance from an evolutionary perspective leads to better predictions of treatment outcomes. The objectives of this study were to develop a computational framework to analyze tumor longitudinal measurements and recapitulate the individual evolutionary dynamics in metastatic colorectal cancer (mCRC) patients. A stochastic modeling framework was developed to depict the whole spectrum of tumor evolution prior to diagnosis and during and after therapy. The evolutionary model was optimized using a nonlinear mixed effect (NLME) method based on the longitudinal measurements of liver metastatic lesions from 599 mCRC patients. The deterministic limits in the NLME model were applied to optimize the stochastic model for each patient. Cox proportional hazards models coupled with the least absolute shrinkage and selection operator (LASSO) algorithm were applied to predict patients' progression-free survival (PFS) and overall survival (OS). The stochastic evolutionary model well described the longitudinal profiles of tumor sizes. The evolutionary parameters optimized for each patient indicated substantial interpatient variability. The number of resistant subclones at diagnosis was found to be a significant predictor to survival, and the hazard ratios with 95% CI were 1.09 (0.79–1.49) and 1.54 (1.01–2.34) for patients with three or more resistant subclones. Coupled with several patient characteristics, evolutionary parameters strongly predict patients' PFS and OS. A stochastic computational framework was successfully developed to recapitulate individual patient evolutionary dynamics, which could predict clinical survival outcomes in mCRC patients. Significance: A data analysis framework depicts the individual evolutionary dynamics of mCRC patients and can be generalized to project patient survival outcomes.

Background Methamphetamine (METH) is a highly addictive psychostimulant that strongly activates dopamine receptor signaling in the nucleus accumbens (NAc). However, how dopamine D1 and D2 receptors (D1Rs and D2Rs, respectively) as well as downstream signaling pathways, such as those involving Rac1 and Cdc42, modulate METH-induced behavioral and structural plasticity is largely unknown. Methods Using NAc conditional D1R and D2R deletion mice, Rac1 and Cdc42 mutant viruses, and a series of behavioral and morphological methods, we assessed the effects of D1Rs and D2Rs on Rac1 and Cdc42 in modulating METH-induced behavioral and structural plasticity in the NAc. Results D1Rs and D2Rs in the NAc consistently regulated METH-induced conditioned place preference, locomotor activation, and dendritic and spine remodeling of medium spiny neurons but differentially regulated METH withdrawal–induced spatial learning and memory impairment and anxiety. Interestingly, Rac1 and Cdc42 signaling were oppositely modulated by METH, and suppression of Rac1 signaling and activation of Cdc42 signaling were crucial to METH-induced conditioned place preference and structural plasticity but not to locomotor activation. D1Rs activated Rac1 and Cdc42 signaling, while D2Rs inhibited Rac1 signaling but activated Cdc42 signaling to mediate METH-induced conditioned place preference and structural plasticity but not locomotor activation. In addition, NAc D1R deletion aggravated METH withdrawal–induced spatial learning and memory impairment by suppressing Rac1 signaling but not Cdc42 signaling, while NAc D2R deletion aggravated METH withdrawal–induced anxiety without affecting Rac1 or Cdc42 signaling. Conclusions D1Rs and D2Rs differentially regulate Rac1 and Cdc42 signaling to modulate METH-induced behavioral plasticity and the structural remodeling of medium spiny neurons in the NAc.

Neuroplastin 65 (Np65) is a brain-specific cell adhesion molecule that is highly expressed in the hippocampus, amygdala, and cortex, regions of the brain that are associated with memory and emotions. However, the role of Np65 in regulation of emotional behavior is still unclear. In the present study, we show that Np65 knock-out (Np65 KO) mice display enhanced anxiety-like behavior, a reduction in some aspects of depressive-like behaviors, and increased sociability and memory. Biochemical investigations revealed that Np65 KO mice show increased adult-born neurons and proliferation in the hippocampus. In addition, the level of 5-hydroxytryptamine (5-HT) in the hippocampus was reduced. The expression of tryptophan hydroxylase 2 in the brainstem and the expression of the 5-HT3A receptor were also decreased. Electrophysiological recordings confirmed an impaired maintenance of long-term potentiation in the hippocampus of Np65 KO mice. Together, our findings uncover a role for Np65 in regulating anxiety- and depressive-like behaviors and suggest that Np65 may be essential for the maintenance of emotional stability, indicating that it might be an attractive potential target for treatment of psychiatric disorders.

Critical limb ischemia (CLI) is the most advanced clinical stage of peripheral vascular disease with high mobility and mortality. CLI patients suffer from lower extremity rest pain, ulceration, and gangrene caused by insufficient blood and oxygen supply. Seeking for effective biomarkers and therapeutic targets is of great significance for improving the life quality of CLI patients. The circadian clock has been reported to be involved in the progression of kinds of cardiovascular diseases. Whether and how circadian genes play a role in CLI remains unknown. In this study, by collecting femoral artery and muscle specimens of CLI patients who underwent amputation, we confirmed that the circadian gene Bmal1 is downregulated in the CLI femoral artery and ischemic distal lower limb muscle. Furthermore, we verified that Bmal1 affects CLI by regulating lipid metabolism, inflammation, and angiogenesis. A hindlimb ischemia model performed in wild-type and Bmal1−/− mice confirmed that Bmal1 disruption would lead to impaired angiogenesis. In vitro experiments indicated that the decreased expression of Bmal1 would increase ox-LDL uptake and impair endothelial cell functions, including proliferation, migration, and tube formation. As for mechanisms, Bmal1 represses inflammation by inhibiting lipid uptake and by activating IL-10 transcription and promotes angiogenesis by transcriptionally regulating VEGF expression. In conclusion, we provide evidence that the circadian gene Bmal1 plays an important role in CLI by inhibiting inflammation and promoting angiogenesis. Thus, Bmal1 may be an effective biomarker and a potential therapeutic target in CLI.

Background: IRP2 (Iron regulatory protein 2) deficiency in mice and humans causes microcytic anemia and neurodegeneration due to functional cellular iron depletion. Our previous in vitro data have demonstrated that Irp2 depletion upregulates hypoxia-inducible factor subunits Hif1α and Hif2α expression and inhibition of Hif2α rescues Irp2 ablation-induced mitochondrial dysfunction and inhibition of Hif1α suppresses the overdose production of lactic acid derived from actively aerobic glycolysis. We wonder whether Hif1α and Hif2α are also elevated in vivo, and if they are elevated, are they related to the neurodegenerative disorder of Irp2-/- mice.Results: In this study, we confirmed the upregulated Hif2α, not Hif1α, in tissues, particularly, the central nervous system including the mainly affected cerebellum and spinal cord of Irp2-/- mice. Consistent with this observation, inhibition of Hif2α by PT-2385, not Hif1α by PX-478, prevented the neurodegenerative symptoms, which was proved by Purkinje cells arrangement from the shrunken and irregular to the full and regular array. PT-2385 treatment did not only modulate mitochondrial morphology and quality in vivo, but also suppressed the glycolysis. Consequently, the shift of energy metabolism from glycolysis to oxidative phosphorylation reversed. Conclusions: Our results indicate that Irp2 depletion-induced Hif2α is alone, in vivo, in charge of the switch between oxidative phosphorylation and glycolysis, suggesting that, for the first time to our knowledge, Hif2α is a clinically potential target in the treatment of IRP2 deficiency-induced neurodegenerative syndrome.

Purpose The mouse retina is considered a remarkable model for studying gene functions. However, variations in genetic background influence phenotypes in the mammalian retina. Therefore this study aimed to investigate the effects of the genetic background on the nuclear architecture of photoreceptor cells and the light-induced behavior in C57BL/6, 129 × 1/svj, and ICR mice. Methods The nuclear architecture of photoreceptor cells was investigated using various staining methods on postnatal day 21 (P21). Murine behavior was observed using a light-dark compartment test. Results The outer nuclear layer and retina were significantly thicker in C57BL/6 mice than in 129 × 1/svj mice. The percentage of photoreceptors with one chromocenter was significantly higher in C57BL/6 mice than in 129 × 1/svj and ICR mice on P21. The numbers of photoreceptor cells in C57BL/6 and ICR mice were significantly higher than those in 129 × 1/svj mice. The behavior test revealed that the walking distance and velocity in the light compartment were increased in C57BL/6 and ICR mice compared to 129 × 1/svj mice. Conclusions Different mouse strains had a distinct nuclear architecture of photoreceptors on P21, and C57BL/6 and ICR mice were more active than 129 × 1/svj mice in response to light-induced stress. Translational Relevance This study demonstrates a technique for assessing retinal structures and nuclear architecture in various strains of mice, which are often used to model human retinal disease. Hence, this study may help to elucidate the effect of genetic or disease-induced variance in retinal architecture and the organization of photoreceptor nuclear content on visual function in humans.

OBJECTIVE: Comparison of remifentanil versus propofol for sedation during transcatheter aortic valve replacement (TAVR) procedures to analyze the risk of sedation related hypoxemia and hypotension. Secondary outcomes included the rate of conversion to general anesthesia, procedure length, rate of intensive care unit (ICU) admission, ICU and hospital length of stay, and thirty-day mortality. DESIGN: Retrospective cohort study. SETTING: A single tertiary teaching hospital. PARTICIPANTS: Two hundred and fifty nine patients who had propofol or remifentanil sedation for TAVR between March 2017 and March 2020. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: There were 130 patients (50.2%) in the propofol cohort and 129 patients (49.8%) in the remifentanil cohort. The primary outcomes were oxygen saturation nadir values and vasopressor infusion use. Remifentanil was associated with a lower oxygen saturation nadir, as compared to propofol (91.3% vs. 95.4%, p < 0.001). Risk factors associated with hypoxemia (defined as < 92%) were body mass index (p = 0.0004), obstructive sleep apnea (p = 0.004), and remifentanil maintenance (p < 0.001). Vasopressor infusion use was significantly higher with propofol (64.9% vs. 8.5%, p < 0.001). Propofol maintenance and ACEi/ARB use were the only variables identified as risk factors for vasopressor use (p < 0.001 and p = 0.009). CONCLUSIONS: For patients undergoing TAVR with conscious sedation, remifentanil was associated with more hypoxemia while propofol was associated with a higher rate of vasopressor use.

BackgroundPostpartum depression (PPD) has been identified as a recognized public health problem that may adversely affect mothers, infants, and family units. Recent studies have identified risk factors for PPD in Westerners; however, societal and cultural differences between China and the West could, potentially, lead to differences in risk factors for PPD. No comprehensive study has been conducted to collect all the evidence to provide estimates of psychological and social risk factors in China. Therefore, this study aimed to quantitatively assess all studies meeting the review’s eligibility criteria and identify the psychological and social risk factors for PPD in Chinese women.MethodsThe following databases were used in the literature search from their inception until December 2020: PubMed, Embase, Foreign Medical Literature Retrieval Service (FMRS), China Science and Technology Journal Database (VIP), China National Knowledge Infrastructure (CNKI), and China Biology Medicine disc (CBM). The quality was assessed through Newcastle-Ottawa quality assessment scale. The I2statistic was used to quantify heterogeneity. We extracted data for meta-analysis and generated pooled-effect estimates from a fixed-effects model. Pooled estimates from a random-effects model were also generated if significant heterogeneity was present. Funnel plot asymmetry tests were used to check for publication bias. Statistical analysis was conducted using Review Manager version 5.3 software.ResultsFrom a total of 1175 identified studies, 51 were included in the analysis. Prenatal depression (OR 7.70; 95% CI 6.02–9.83) and prenatal anxiety (OR 7.07; 95% CI 4.12–12.13) were major risk factors for PPD. A poor economic foundation (OR 3.67; 95% CI 3.07–4.37) and a poor relationship between husband and wife (OR 3.56; 95% CI 2.95–4.28) were moderate risk factors. Minor risk factors included a poor relationship between mother-in-law and daughter-in-law (OR 2.89; 95% CI 2.12–3.95), a lack of social support (OR 2.57; 95% CI 2.32–2.85), unplanned pregnancy (OR 2.55; 95% CI 2.08–3.14), and poor living conditions (OR 2.44; 95% CI 1.92–3.10), mother-in-law as the caregiver (1.95; 95% CI 1.54–2.48) .ConclusionsThis study demonstrated a number of psychological and social risk factors for PPD in Chinese women. The major and moderate risk factors are prenatal depression, prenatal anxiety, a poor economic foundation, and a poor relationship between husband and wife. These findings have potential implications for informing preventive efforts and modifying screening to target at-risk populations.

Chinese ginseng (Panax ginseng C. A. Meyer) is a highly cherished traditional Chinese medicine, with several confirmed medical effects and many more asserted health-boosting functions. Somatic chromosomal instability (CIN) is a hallmark of many types of human cancers and also related to other pathogenic conditions such as miscarriages and intellectual disabilities, hence, the study of this phenomenon is of wide scientific and translational medical significance. CIN also ubiquitously occurs in cultured plant cells, and is implicated as a major cause of the rapid decline/loss of totipotency with culture duration, which represents a major hindrance to the application of transgenic technologies in crop improvement. Here, we report two salient features of long-term cultured callus cells of ginseng, i.e., high chromosomal stability and virtually immortalized totipotency. Specifically, we document that our callus of ginseng, which has been subcultured for 12 consecutive years, remained highly stable at the chromosomal level and showed little decline in totipotency. We show that these remarkable features of cultured ginseng cells are likely relevant to the robust homeostasis of the transcriptional expression of specific genes (i.e., genes related to tissue totipotency and chromosomal stability) implicated in the manifestation of these two complex phenotypes. To our knowledge, these two properties of ginseng have not been observed in any animals (with respect to somatic chromosomal stability) and other plants. We posit that further exploration of the molecular mechanisms underlying these unique properties of ginseng, especially somatic chromosomal stability in protracted culture duration, may provide novel clues to the mechanistic understanding of the occurrence of CIN in human disease.

Background: Delivery of long-acting nanoformulated antiretroviral drugs (ARVs) to human immunodeficiency virus type one cell and tissue reservoirs underlies next generation antiretroviral therapeutics. Nanotheranostics, comprised of trackable nanoparticle adjuncts, can facilitate ARV delivery through real-time drug tracking made possible through bioimaging platforms. Methods: To model HIV-1 therapeutic delivery, europium sulfide (EuS) nanoprobes were developed, characterized and then deployed to cells, tissues, and rodents. Tests were performed with nanoformulated rilpivirine (NRPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used clinically to suppress or prevent HIV-1 infection. First, CD4+ T cells and monocyte-derived macrophages were EuS-treated with and without endocytic blockers to identify nanoprobe uptake into cells. Second, Balb/c mice were co-dosed with NRPV and EuS or lutetium177-doped EuS (177LuEuS) theranostic nanoparticles to assess NRPV biodistribution via mass spectrometry. Third, single photon emission computed tomography (SPECT-CT) and magnetic resonance imaging (MRI) bioimaging were used to determine nanotheranostic and NRPV anatomic redistribution over time. Results: EuS nanoprobes and NRPV entered cells through dynamin-dependent pathways. SPECT-CT and MRI identified biodistribution patterns within the reticuloendothelial system for EuS that was coordinate with NRPV trafficking. Conclusions: EuS nanoprobes parallel the uptake and biodistribution of NRPV. These data support their use in modeling NRPV delivery to improve treatment strategies.

Cadmium (Cd) is a heavy metal, which is widely used in the industry and daily life. It has a long half-life, so large amounts of Cd can accumulate in humans and become toxic. Chlorogenic acid (CGA) can eliminate free radicals and inhibit lipid peroxidation and is mainly used to prevent metal toxicity. In the present study, mice are given CGA by intraperitoneal injection or gavage, respectively, to explore the mechanism of preventing Cd toxicity. In acute Cd-exposed mice, CGA treatment (ip) alleviated Cd-induced oxidative damage and reduced the production of NO and MPO in the liver and kidney tissues, while TLR4 expression levels did not change significantly. After 8 weeks of Cd exposure, CGA administration (gavage) significantly alleviated gut dysbiosis by decreasing the Firmicutes to Bacteroidetes ratio, enhancing the relative abundances of bacteria, including Ruminiclostridium_9, Alloprevotella, and Rikenella, and inhibiting the activation of the TLR4/MyD88/NF-κB signaling pathway. These findings suggested that protection mechanisms underlying the oral administration of CGA against the Cd-induced hepatorenal injury was related to the regulation of the intestinal flora balance. CGA can be used as an effective component in daily diet to prevent Cd toxicity.